TRANSCRIPTION FACTOR: MECHANISM OF ACTION, TYPES, FUNCTIONS - BIOLOGY - 2024

A transcription factor is a regulatory "accessory" protein necessary for gene transcription. Transcription is the first step of gene expression and involves the transfer of the information contained in DNA to an RNA molecule, which is subsequently processed to give rise to gene products.

RNA polymerase II is the enzyme responsible for the transcription of most eukaryotic genes and produces, in addition to some small RNAs, messenger RNAs that will later be translated into proteins. This enzyme requires the presence of a type of transcription factors known as general or basal transcription factors.

Transcription factor type «Leucine closure» (Source: I, Splette via Wikimedia Commons)

However, these are not the only transcription factors that exist in nature, since there are “non-general” proteins, both in eukaryotes and in prokaryotes and archaea, that are involved in the regulation of tissue-specific gene transcription (in multicellular organisms) or in the regulation of gene activity in response to various stimuli.

These transcription factors are highly important effectors, and can be found in virtually all living organisms, since they represent the main source of regulation of gene expression.

Detailed studies of different transcription factors in different types of living organisms indicate that they have a modular structure, in which a specific region is responsible for the interaction with DNA, while the others produce the stimulatory or inhibitory effects.

The transcription factors, then, participate in the modeling of gene expression patterns that has nothing to do with changes in the DNA sequence, but with epigenetic changes. The science that is responsible for studying these changes is known as epigenetics.

Mechanism of action

In order to perform their functions, transcription factors must be able to specifically recognize and bind to a particular DNA sequence to positively or negatively influence the transcription of that region of DNA.

General transcription factors, which are basically the same for the transcription of all type II genes in eukaryotes, assemble first on the promoter region of the gene, thus directing the positioning of the polymerase enzyme and the "opening" of the double propeller.

The process takes place in several consecutive steps:

- Binding of the general transcription factor TFIID to a sequence of repeats of thymine (T) and adenine (A) in the gene known as "the TATA box"; this causes a distortion of the DNA that is necessary for the binding of other proteins to the promoter region.

- Subsequent assembly of other general factors (TFIIB, TFIIH, TFIH, TFIIE, TFIIF, etc.) and of RNA polymerase II, forming what is called the transcription initiation complex.

- Release of the initiation complex, phosphorylation of the polymerase by factor TFIIH and the beginning of the transcription and synthesis of an RNA molecule from the sequence of the gene that is transcribed.

Activation and repression of transcription

As discussed, "non-general" transcription factors can regulate gene expression, either positively or negatively.

Activation

Some of these proteins contain, in addition to the structural DNA-binding domains, other motifs known as activation domains, which are rich in acidic amino acid residues, glutamine or proline residues.

These activation domains interact with elements of the complex of general transcription factors or with related coactivator molecules that interact directly with the complex. This interaction results either in the stimulation of the assembly of the transcriptional complex or in the increase of its activity.

Repression

Most transcription factors inhibit transcription by interfering with the activity of positively acting transcription factors, blocking their stimulatory effect. They can work by blocking the binding of positive factor to DNA or by acting on factors that inactivate the chromatin structure.

Other inhibitory factors act by directly blocking transcription, without blocking the action of any activating transcriptional factor; and they decrease the basal level of transcription, to a level even lower than that achieved in the absence of the activating factors.

Like activator proteins, repressor factors act directly or indirectly with basal or general transcription factors.

Types

Although most transcription factors are classified according to the characteristics or identity of their DNA-binding domains, there are some, also classified as transcription factors, that do not interact directly with DNA and are known as transcription factors. "Indirect".

Direct transcription factors

They are the most common transcription factors. They have DNA-binding domains and can activate or inhibit gene expression by binding to specific regions of DNA. They differ from each other especially with respect to their DNA-binding domains and their state of oligomerization.

The most studied and recognized families of this type of factor are:

Helix-Turn-Helix (“ helix-turn-helix ”, HTH)

This was the first family of factors with DNA-binding domains to be discovered, and it is present in many eukaryotic and prokaryotic proteins. Its recognition motif consists of an α helix, a spin, and a second α helix.

They have conserved glycine domains in the region of the turn and also some hydrophobic residues that help stabilize the arrangement of the two helixes in the HTH unit.

Homeodomain

It is present in a large number of eukaryotic regulatory proteins. The first sequences were recognized in Drosophila developmental regulatory proteins. This domain contains an HTH motif to bind DNA and an additional α-helix, in addition to an extended N-terminal arm.

Zinc Fingers

They were discovered in the Xenopus transcription factor TFIIIA and have been shown to participate in many aspects of eukaryotic gene regulation. They are found in proteins induced by differentiation and growth signals, in proto-oncogenes, and in some general transcription factors.

They are characterized by the presence of batch repeats of 30 residue zinc finger motifs containing various cysteine ​​and histidine residues.

Steroid receptors

This family includes important regulatory proteins that, in addition to having a domain for hormone binding, possess a DNA binding domain and generally act as transcriptional activators.

The binding domains contain 70 residues, among which 8 are conserved cysteine ​​residues. Some authors consider that these factors could form a pair of zinc fingers, given the presence of two sets of four cysteines.

Leucine closure and helix-loop-helix (“ helix-loop-helix”)

These transcription factors are involved in differentiation and development and function by the formation of a heterodimer. The leucine closure domain is observed in various eukaryotic proteins and is characterized by two subdomains: the leucine closure that mediates dimerization and a basic region for DNA binding.

Β sheet motifs

They are mainly found in eukaryotic factors and are distinguished by binding to DNA by antiparallel β-sheets.

Indirect transcription factors

This type of transcription factor exerts its regulatory effects on gene expression not through direct interaction with DNA, but through protein-protein interactions with other transcription factors that do interact with DNA. That is why they are called "indirect".

The first to be described was the trans-activator of the herpes simplex virus (HSV) known as VP16, which binds to factor Oct-1 when cells are infected with this virus, stimulating the transcription of a specific gene.

Factors of this type, like those that do bind to DNA, can activate or repress gene transcription, which is why they are called “coactivators” and “corepressors”, respectively.

Regulation

These proteins can be regulated at two levels: in their synthesis and in their activity, which depends on different variables and multiple situations.

Regulation of synthesis

The regulation of its synthesis may be related to the tissue-specific expression of certain transcription factors. An example of this may be the MyoD factor, synthesized only in skeletal muscle cells and which is necessary for the differentiation of their undifferentiated fibroblast precursors.

Although the regulation of synthesis is used fundamentally for the control of gene expression in specific cell types and tissues, this is not the only way, since the synthesis of factors involved in the induction of genes that participate in the response is also regulated. to various stimuli.

Regulation of activity

Another regulatory mechanism for transcription factors is the regulation of their activity, which has to do with the activation of other pre-existing transcription factors that exert positive or negative effects on the activity of a particular factor.

The activation of these "secondary" factors usually occurs through different mechanisms such as ligand binding, alterations in protein-protein interactions, phosphorylation, among others.

Roles and importance

Transcription factors participate in a wide variety of processes such as embryonic development, growth and differentiation, control of the cell cycle, adaptation to fluctuating environmental conditions, maintenance of cell and tissue specific protein synthesis patterns, etc.

In plants, for example, they have important functions in defense and in response events to different types of stress. Osteogenesis in animals has been determined to be controlled by transcription factors, as well as many other differentiation processes of different cell lines.

Given the importance of these proteins in organisms, it is not uncommon to think that alterations in these regulatory elements will cause serious pathological alterations.

In the case of humans, the pathologies associated with transcription factors can be developmental disorders (due to mutations that cause inactivation of transcription factors, for example), disorders in the hormonal response or cancers.

References

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